EFFECTS OF PROSTAGLANDIN E(2) ON THO-TYPE HUMAN T-CELL CLONES - MODULATION OF FUNCTIONS OF NUCLEAR PROTEINS INVOLVED IN CYTOKINE PRODUCTION

The effects of prostaglandin E(2) (PGE(2)) on cytokine production and proliferation of the CD4(+) human helper T cell clone SP-B21 were investigated. In cells stimulated with anti-CD3 mAb, PGE(2) inhibited cell proliferation and the production of all the cytokines examined. Addition of rIL-2 fully restored the proliferative response and partially restored the production of IL-4 and IL-5, but not that of other cytokines. In contrast, in cells stimulated with phorbol myristate acetate (PMA)/A23187, PGE(2) enhanced the production of IL-4 and IL-5, and only partially inhibited the production of other cytokines. Therefore, the effects of PGE(2) vary depending on the mode of T cell activation, and the IL-4 and IL-5 are regulated differently from other cytokines. In a mobility shift assay, only the NF-kappa B (p50/p50) homodimer was observed in a complex formed with the kappa B sequence in unstimulated SP-B21 cells. When cells were stimulated with anti-CD3 mAb or PMA/A23187, a complex formation of NF-kappa B (P50/p65) heterodimer with the kappa B sequence was induced. Interestingly, PGE(2) or di-butyryl (Bt(2))cAMP abolished the binding of NF-kappa B (p50/p65) heterodimer to the kappa B sequence in cells stimulated with anti-CD3 mAb but not with PMA/A23187. Our results suggest that the target of PGE(2) action is a component in the signal transduction pathway leading to the activation of protein kinase C. However, the inhibition of the T cell activation signals by PGE(2) is selective. PGE(2) enhanced the complex formation with NF-AT, AP-1 and CLEO sequences when the cells were activated by either anti-CDS mAb or PMA/A23187 stimulation. It seems therefore that PGE(2), by elevating cAMP levels, interferes with the activation pathway for NF-kappa B but not for NF-AT, AP-1 or CLEO binding protein.